title: Propentofylline and iloprost suppress the production of TNF-alpha by macrophages but fail to ameliorate experimental autoimmune encephalomyelitis in Lewis rats.
abstract: Intracellular cAMP levels can be elevated by activation of cAMP-generating adenylate cyclase (AC) or inhibition of cAMP-cleavage by phosphodiesterases. Elevation of intracellular cAMP levels in immune cells inhibits production of some Th1-cytokines, particularly TNF-alpha, and results mainly in downregulation of the immune response. Experimental autoimmune encephalomyelitis (EAE) of Lewis rats is a disease mediated by type 1 T helper lymphocytes and macrophages and serves as a model of multiple sclerosis. In EAE we therefore tested the immunomodulatory potency of an AC-activating, stable prostacyclin analogue, iloprost, and of a potent and non-selective inhibitor of phosphodiesterases, propentofylline, which also has neuroprotective properties. Preventive treatment of Lewis rats with propentofylline (2 x 10 or 12.5 mg/ kg/d), iloprost (2 x 10 or 12.5 micrograms/kg/d), or both did not significantly ameliorate clinical or histological signs of EAE actively induced by immunization with myelin basic protein (MBP) in complete Freund's adjuvant. Furthermore, adoptive transfer EAE (AT-EAE), passively induced by injection of encephalitogenic MBP-specific Th1 lymphocytes, was not altered in its course by the combined application of iloprost (2 x 10 micrograms/kg/d) and propentofylline (2 x 20 mg/kg/d) starting on the day of cell transfer. In vitro assays demonstrated that iloprost strongly and propentofylline moderately inhibited the production of TNF-alpha by macrophages and that iloprost in vivo similarly suppressed TNF-alpha secretion, although this effect was limited to a few hours after a single injection. In contrast to macrophages, TNF-alpha production by antigen-activated encephalitogenic T helper line cells in vitro was completely resistant to modulation by these agents. In addition, the presence of iloprost, propentofylline, or both drugs during activation of the line cells in vitro did not impair their encephalitogenicity in vivo. The findings delineate immunomodulatory effects of both substances, particularly of iloprost, but fail to support a possible therapeutic role of these agents in autoimmune inflammation of the central nervous system.
authors.affiliation: Department of Neurology, Julius-Maximilians Universität Würzburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Jung
authors.forename: T
authors.initials: T
authors.lastname: Donhauser
authors.forename: K V
authors.initials: KV
authors.lastname: Toyka
authors.forename: H P
authors.initials: HP
authors.lastname: Hartung
mesh_terms: D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D004357:Drug Synergism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D016285:Iloprost / Q000494:pharmacology*; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D004676:Myelin Basic Protein / Q000633:toxicity; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D014665:Vasodilator Agents / Q000494:pharmacology*; D014970:Xanthines / Q000494:pharmacology*
chemical_list: D000897:Anti-Ulcer Agents; D004676:Myelin Basic Protein; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D014970:Xanthines; C032114:propentofylline; D010727:Phosphoric Diester Hydrolases; D016285:Iloprost